Neuroprotective role of ERK1/2 and ERK5 in a dopaminergic cell line under basal conditions and in response to oxidative stress.

Loss of motor function in Parkinson's disease is due in part to degeneration of dopamine (DA) neurons. Pharmacological evidence suggests that the mitogen-activated protein kinase signaling pathways involving extracellular signal-regulated kinases (ERKs) play important roles in neuroprotection of DA neurons. However, the relative roles of the several ERK isoforms in the viability of DA neurons have not yet been determined. In the present study, we investigated the contributions of ERK5, as well as ERK1/2, to MN9D cell survival under basal conditions and in response to 6-hydroxydopamine (6-OHDA). We observed that U0126, an inhibitor of ERK activation, decreased basal survival of these cells. To differentiate between ERK1/2 and ERK5, cells were transfected with a dominant negative form of either ERK5 or MEK1, the upstream activator of ERK1/2. Transfection of MN9D cells with either dominant negative construct mimicked U0126, reducing cell survival. Moreover, transfection of the cells in such a way as to increase ERK5 or ERK1/2 activity inhibited 6-OHDA-induced cell death, although this effect was significant only in the case of ERK1/2 activation. These studies suggest that activations of ERK5 and ERK1/2 both promote basal DA cell survival and that ERK1/2 also protects DA cells from oxidative stress. These are the first studies to demonstrate a role for ERK5 in DA neuronal survival and to investigate the relative roles of ERK1/2 and ERK5 in basal DA survival and neuroprotection from oxidative stress. Copyright 2006 Wiley-Liss, Inc.